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Drug Production Gets Aquatic

Green algae are cheap to grow, hard to kill, and quick to thrive. Such traits make the tiny plants an ideal production factory, one that is already being extensively explored as a source for biofuels. But a few people are also looking to algae to do a completely different brand of work: the manufacturing of therapeutic drugs, a system that could one day produce large quantities of certain drugs at one-thousandth of today’s costs.

Manufacturing plant: The little green alga Chlamydomonas reinhardtii can be engineered to produce proteins for use in therapeutic drugs.

A huge number of so-called biologic drugs, made up of proteins rather than small molecules, are produced, en masse, by bacteria, yeast, or mammalian cell culture–the cells produce proteins that are processed and turned into therapies for cancer, multiple sclerosis, and diabetes, among many other diseases. But such methods can be expensive to set up and maintain: Feeding them requires large amounts of nutrients, sustaining them requires large amounts of energy, and creating sterile facilities is a costly proposition. Stephen Mayfield, director of the San Diego Center for Algae Biotechnology at the University of California at San Diego, believes that algae, which subsist on sunlight and carbon dioxide in the air, could be an ideal and cost-effective substitute.

In a paper published in the Plant Biotechnology Journal, Mayfield and his colleagues looked at the versatility of the green alga Chlamydomonas reinhardtii in order to determine whether it had the potential to act as a robust drug factory. They inserted genes for production of seven different therapeutic proteins currently being made in yeast, bacteria, and mammalian cells, including interferon (for multiple sclerosis) and proinsulin (for diabetes). Of the seven, the algae produced four proteins at levels high enough for commercial use and in forms that were identical to those made by bacterial and mammalian cell systems, and are just as easy to isolate and concentrate.

Complicated proteins that are produced in mammalian cell culture, such as the potent multiple sclerosis drug Tysabri, currently cost an estimated $150 or more per gram of protein. (The number is estimated because few companies release such statistics.) In green algae, Mayfield says, it’s closer to a nickel. “That’s because it’s a plant and it grows in minimal media, pulling carbon dioxide out of the air and using sunlight for its energy source.”

In addition to producing drugs more cheaply, algae plants are cheaper to build. Startup costs for mammalian cell culture plants are the “biggest bottleneck in developing new protein therapeutic drugs,” says Mayfield. “Clinical trials are expensive, but before you even get to the clinic, you have to invest $600 million to build a facility to produce it.”

Unlike the less-evolved bacterial cells, algae are particularly good at folding complex proteins. In fact, even mammalian cells can’t fold certain proteins correctly and require post-production processing to refold them into the correct shape. “This really opens the way to a whole new set of therapeutics,” says George Oyler, a biochemist who’s coordinating the algae research efforts at the University of Nebraska-Lincoln.

Earlier work by Mayfield has shown that algae can also produce human monoclonal antibodies, complex proteins that are produced in mammalian cells and are now being used in some of the most expensive (but effective) cancer treatments. “There are upwards of 80 to 100 of those antibodies in various clinical trials or on the market,” says Oyler. “But the cheapest of those antibodies are on the order of $10,000 or more for a course of therapy. This may open up an alternate platform.”

“There are advantages and disadvantages to algae, just like with other systems,” says Michael Betenbaugh, a biochemical engineer at Johns Hopkins University who specializes in cell protein production. “The systems that are out there already do a pretty good job at making a lot of these proteins. So algae has some stiff competition.” Yeast and bacteria, he notes, are pretty inexpensive, and their culture systems are tried and true–at least for the simpler proteins that don’t require complex folding. But he agrees that the cost advantage over mammalian cells is a substantial one.

Betenbaugh also points out that, unlike mammalian cells, algae produce proteins without attaching sugars to them, a process called glycosylation that’s common to mammalian cells and one that’s often required for the human body to fully utilize and process a molecule. For now, however, Mayfield believes he can avoid this issue: The proteins he’s expressing in algae are ones that are effective without glycosylation, and in the future he thinks it should be possible to do further genetic modifications that allow the plant cells to attach human-like sugars, something researchers have already done in yeast.

Mayfield agrees that it’s not worth messing with a good system, especially when drugs such as insulin are already produced at costs competitive to what algae could do. But with the more complex drugs, algae show great potential. “The most important thing about this paper is that it shows we’re ready for prime time,” he says. He hopes to produce, purify, and test the algae-produced proteins in animal models later this year, and already has researchers in developing nations, such as China and India, interested in the technology and eagerly awaiting his results.